Tropane-2-carboxylates and derivatives

ABSTRACT

TROPANE DERIVATIVS HAVING A PHENYL OR SUBSTITUTED PHENYL GROUP IN THE 3-POSITION AND A CARBO-LOWER-ALKYOXY GROUP IN THE 2-POSITION, POSSESSING LOCAL ANESTHETIC AND/ OR STIMULANT ACTIVITY, ARE PREPARED BY REACTING AN ANHYDROECGONINE LOWER-ALKYL ESTER WITH AN ARYMAGNESIUM HALIDE.

United States Patent "Ofice 3,813,404- Patented May 28, 1974 US. Cl.260-292 9 Claims ABSTRACT OF THE DISCLOSURE Tropane derivatives having aphenyl or substituted phenyl group in the 3-position and acarbo-lower-alkoxy group in the 2-position, possessing local anestheticand/ or stimulant activity, are prepared by reacting an anhydroecgoninelower-alkyl ester with an arylmagnesium halide.

This invention relates to novel tropane derivatives, and in particularis concerned with tropanes having a phenyl or substituted phenyl groupin the 3-position and a carbolower-alkoxy group in the 2-position.

The compounds of the invention have the formula CH- C -R' K (3 (1) 1wN-R" H-Ar (5) (4) CH CH2 I wherein:

one of R and R is hydrogen and the other of R and R iscarbo-lower-alkoxy;

R" is hydrogen or lower-alkyl;

Ar is phenyl or phenyl substituted by from one to two substituentsselected from the group consisting of loweralkyl, lower-alkoxy, fluoro,chloro, and hydroxy.

The compounds of the invention, if derived by synthesis from naturalsources will be optically active. However, optically inactive racemicmixtures can be obtained by total synthesis and these in turn can beresolved by conventional procedures to obtain both optical isomers, onebeing identical to the enantiomer obtained from natural sources and theother the unnatural enantiomer.

The compounds of formula I where R" is lower-alkyl, R and R have themeanings given above, and Ar is phenyl or phenyl substituted by from oneto two substituents selected from the group consisting of lower-alkyl,lower-alkoxy,

fluoro, or chloro can be prepared by reacting a compound of the formulaCHr-CH-C-C 0 O-lower-alkyl wherein R" is lower-alkyl with Ar-magnesiumhalide. There is thus produced a mixture of isomers of formula I, theisomerism involving the orientation of the groups in the 2-position. Theisomers can be separated by chromatographic procedures, or,alternatively, by a quarterm'zation procedure using a loweralkyl orbenzyl halide, whereby the 2a-carboxylate (equatorial) isomer isselectively quaternized forming a water-soluble salt, readily removed bypartitioning the mixture between water and an organic solvent. Theunquaternized -2p-carboxylate (axial) isomer remains in the organicsilvent and can be isolated therefrom. The loweralkyl halidequaternizing agent can have from one to four carbon atoms, and thehalide can be chloride, bromide or iodide.

In the reaction of a compound of formula II with a Grignard reagent, asmall quantity of byproduct of formula III:

III

is formed, resulting from the reaction of a second molecule of Grignardreagent with the carbo-lower-alkoxy group. The byproducts of formula IIIare readily separated from the compounds of formula I by fractionaldistillation, the former being the less volatile.

The compounds of formula I wherein AI is hydroxyphenyl are prepared byacid cleavage of the compounds of formula I wherein AI islower-alkoxyphenyl. Some concurrent hydrolysis of the2-carbo-lower-alkoxy group to a Z-carboxy group may occur, necessitatingre-esterification of the product.

The compounds of formula I wherein R" is hydrogen are prepared from thecompounds of formula I wherein R" is methyl by a demethylation procedureinvolving treatment with 2-chloroethyl chloroformate, followed byreacting the resulting N-(2-chloroethoxycarbonyl) compound with chromousperchlorate.

Pharmacological evaluation of the compounds of formula I has shown thatthey possess local anesthetic activity when tested by the standardintradermal anesthetic test in guinea pigs [Biilbring and Wajda, J.Pharmacol. Exptl. Therap., 85, 78 (1945)]. The compounds have anactivity of the order of 10-20 percent that of cocaine. Further more,the compounds of formula I, where the carbolower-alkoxy group in the2-position has the fi-configuration (axial) and the enantiomorphic formis that derived from natural sources, have been shown to possessstimulant properties when tested by the elfect on locomotor activity inmice according to the method of Aceto et al., J. Pharmacol. Exptl.Therap. 158, 286 (1967); and by the prevention and reversal ofreserpine-induced eyelid ptosis in mice according to the method of Acetoand Harris, Toxicol. Appl. Pharmacol, 7, 329 (1965). For example, thecompound of formula I where R is fl-carbomethoxy, R is hydrogen, R" ismethyl and Ar is phenyl is sixteen times as active as cocaine as astimulant in the locomotor activity test; and the compound where R isfi-carbomethoxy, R is hydrogen, R" is methyl and Ar is p-fluorophenyl issixty-four times as active as cocaine in the locomotor activity test,and five and twenty times as active as cocaine in the reserpine-inducedptosis prevention and reversal tests, respectively.

The compounds of formula I are useful both in the free base form and inthe form of acid-addition salts, and both forms are within the purviewof the invention. The acid-addition salts are simply a more convenientform for use, and in practice, use of the salt form inherently amountsto use of the base form. For pharmaceutical purposes, the acids whichcan be used to prepare the acidaddition salts include preferably thosewhich produce, when combined with the free base, medicinally acceptablesalts, that is, salts whose anions are relatively innocuous to theanimal organism in medicinal doses of the salts, so that the beneficialproperties inherent in the free base are not vitiated by side effectsascribable to the anions. Appropriate medicinally acceptable saltsWithin the scope of the invention are those derived from mineral acidssuch as hydrochloric acid, hydrobromic acid, hydriodic acid, nitricacid, phosphoric acid, sulfarnic acid, and sulfuric acid; and organicacids such as acetic acid, citric acid, tartaric acid, lactic acid,cyclohexanesulfamic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, quinic acid, and the like,giving the hydrochloride, hydrobrornide, hydriodide, nitrate, phosphate,sulfamate, acetate, citrate, tartrate lactate, cyclohexanesulfamatemethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonateand quinate, respectively.

The acid-addition salts of said basic compounds are prepared either bydissolving the free base in aqueous or aqueous-alcohol solutioncontaining the appropriate acid and isolating the salt by evaporatingthe solution, or by reacting the free base and acid in an organicsolvent, in which case the salt separates directly or can be obtained byconcentration of the solution.

Although medicinally acceptable salts of said basic compounds arepreferred for pharmaceutical purposes, all acid-addition salts arewithin the scope of our invention. All acid-addition salts are useful assources of the free base form even if the particular salt per se isdesired only as an intermediate product as for example when. the salt isformed only for purposes of purification or identification, or when itis used as an intermediate in preparing a medicinally acceptable salt byion exchange procedures.

The compounds can be prepared for use by dissolving under sterileconditions salt forms of the compounds in water (or an equivalent amountof a non-toxic acid if the free base is used), or in a physiologicallycompatible aqueous medium such as saline, and stored in ampoules forintramuscular injection. Alternatively, they can be incorporated in unitdosage form as tablets or capsules for oral administration either aloneor in combination with suitable adjuvants such as calcium carbonate,starch, lactose, talc, magnesium stearate, gum acacia, and the like.

The molecular structures of the compounds of this invention wereassigned on the basis of the methods of their synthesis and the study oftheir infrared and nuclear magnetic resonance (NMR) spectra, andconfirmed by the correspondence between calculated and found values forthe elementary analyses for representative examples.

The best mode of carrying out the preparative aspect of the invention isas follows:

To an eificiently stirred solution of 1.0 mole of Grignard reagent(Ar-Mg halide) in 1.0 liter of ether maintained at -20 (13) C. undernitrogen was added a solution of 0.5 mole of anhydroecgonine lower-alkylester (formula II, R" is methyl) in 300 ml. of ether. Stirring wascontinned at this temperature for one hour and the mixture then pouredonto 500 g. of ice. The resulting mixture was acidified with 2 Nhydrochloric acid to dissolve all solid material and the ether layer wasthen separated and discarded. The water layer was made basic withconcentrated ammonium hydroxide and saturated with sodium chloride, andthen extracted three times with ether. The resulting product wasdistilled at 0.4 mm. A minor amount of unchanged anhydroecgonine esterdistilled first, followed 4 by a mixture of the 20candZB-carbo-lower-alkoxy isomers of formula I. The 2-aroyl-3-aryltropanebyproducts of formula III remained behind in the still pot.

If isolation of both the 2aand 2fi-epimers was desired, the mixture ofisomers was chromatographed on silica gel (40 g. per g. of compound)using isopropylamiue-etherpentane (3:30:67) for elution. The Zfl-epimerwas eluted first. If only the Z/E-epimer was wanted, the mixture washeated under reflux for five hours with four volumes of acetone and 1.1equivalent of ethyl iodide. The acetone and excess ethyl iodide wereremoved in vacuo and the residue partitioned between ether and water togive the pure fl-epimer in the ether layer and the quaternary ammoniumsalt of the wepimer in the water layer.

The still pot residue was chromatographed on silica gel to aiford the2fiaroyl-3-aryltropane as a quickly eluted material and the Za-aroylisomer as the more polar component.

The following examples, prepared according to the foregoing procedurewill further illustrate the invention without the latter being limitedthereby.

EXAMPLE 1 Methyl 3p-phenyl-1aH,5aH-tropane-2-carboxylate was preparedfrom ()-auhydroecgonine methyl ester (natural isomer) andphenylmagnesium bromide. The mixture of isomers was obtained in 75%yield and separated by chromatography into ()-rnethyl 3,8 phenyl-laH,SaH tropane-2fi-carboxylate, M.P. 63-645 C. (plates from pentane), [a]=5.3 (1% in chloroform) (16% yield), l,S-naphthalenedisulfonate salt,M.P. 272- 274 C. (dec.), [a] =86.4- (1% in water); and -methyl 3,9phenyl-1QHJaH-trO ane-Zu-carboxylate, M.P. 70-72 C. (prisms frompentane), [a] =+4.6 (2% in chloroform) (46% yield), hydrochloride salt,M.P. 197-198 C. (needles from acetone),

[a] =+31.4- (1% in water).

From the residue from distillation of the crude reaction mixture wasisolated 25 benzoyl 3,8-phenyl-laH,5cxH- tropane, M.P. 179-180" C. (fromether), [a] =+44.1 (1% in chloroform) and 2a-benzoyl-3B-phenyl-1aH,5aHtropane, M.P. 129-130 C. (from ethanol),

[u] =57.9 (1% in chloroform).

EXAMPLE 2 Methyl 3e (p-fiuorophenyl)-1aH,5aH-tropane-2-carboxylate wasprepared from (-)-anhydroecgonine methyl ester andp-fiuorophenylmagnesium bromide. Cuprous chloride (7 mole percent) wasused in this reaction which was run at 10 C. The mixture of isomers wasseparated on a small scale by thick layer chromatography on silica gel,and on a large scale by the selective quaternization process to afiord()-methy1 3fi(p-fiuorophenyl)-lmH, SaH tropane Zfl-carboxylate, M.P.93-945 C. (from pentane), 1,S-naphthalenedisulfonate salt, M.P. 288-290C. (dec.) (from acetonitrile), [41] =83.9 (1% in water); and (+)-methyl3,8-(p-fluorophenyl)-1aH,5aH- tropane 2a-carboxylate, M.P. 70.5-73 C.(from pentane), [a] =+1.1 (5% in chloroform), hydrochloride saltmonohydrate, M.P. -92 C. (needles from ethyl acetate-ether-watermixture), [oz] =+23.7 (1% in water).

-Methyl 3 6- (p-fiuorophenyl) -1aH,5 xH-tropane-2flcarboxylate washydrolyzed to the free acid by heating at reflux a solution of 1.23 g.of the ester in 60 ml. of 2 N hydrochloric acid for 24 hours andconcentrating the mixture to give a crystalline residue. The residue wasrecrystallized from acetone to give 0.83 g. of Bfl-(p-fluorophenyl)-1aH,5aH-tropane-2fl-carboxylic acid in the form of its hydrochloridesalt, M.P. 272-274 C (1% in water).

5 EXAMPLE 3 Methyl 3B (p-methoxyphenyl) 1uH,5aH-tropane-2- carboxylatewas prepared from ()-anhyd roecgonine methyl ester andpmethoxy-phenylmagnesium bromide. The unsaturated ester was added at C.and the reaction was allowed to warm to 25 C. during the stirringperiod. The mixture of epimers was distilled and then separated onsilica plates, to afford methyl 3fi-(p-methoxyphenyl)-1aH,5aH-tropane-2fi-carboxylate, 1.5-naphthalenedisulfonate salt, M.P.288 C. (dec.) (heavy needles from acetonitrile), [oz] =-92.0 (1% inwater; and methyl 3 8-(pmethoxyphenyl) 1uH,5uH-tropane-2a-carboxylate,M.P. 74.5-75.5 C. (blades and needles from pentane), [a] =+9.3 (1% inchloroform).

From the residue from distillation of the crude reaction mixture wasisoltaed 2a (p-methoxybenzoyl) 3/8-(pmethoxyphenyl) 1aH,5aH-tr0pane,M.P. 123-124 C. (pale yellow prisms from ether), [a] =-82.7 1% inchloroform).

- EXAMPLE 4 Isopropyl 318 phenyl-1aH,5aH-tropane-2 3-carboxylate wasprepared from (--)-anhydroecgonine isopropyl ester and phenylmagnesiumbromide in the presence of 5 mole percent of cupric iodide at C. Thecrude, undistilled mixture was chromatographed directly on a silica gelcolumn to give a 20% yield of isopropyl 3p phenyl-laH,SuH-tropane-2B-carboxylate, M.P. 244-245 C. (dec.), fine needles frommethanol-ether, [a] =105.4 (1% in water).

The starting material, (-)-anhydroecgonine isopropyl ester was preparedas follows: A mixture of 50 g. of natural ecgonine hydrochloride and 100ml. of phosphorus oxychloride was heated at reflux for one hour and theexcess phosphorus oxychloride was removed by warming the mixture invacuo. The residue was treated with 350 ml. of isopropyl alcohol andallowed to stand for three days. The solvent was removed, the residuemade basic with 35% sodium hydroxide, and the mixture extracted withether. The oil thus extracted was distilled to give 42 g. of()-anhydroecgonine isopropyl ester, B.P. 87 96 C. (0.8 mm.), [a] =-33.1(1% in chloroform), n 1.4860.

EXAMPLE 5 Isopropyl 3/3 (p-fluorophenyl) 1aH,5uH-tropane-2- carboxylatewas prepared from ()-anhydroecgonine isopropyl ester andp-fiuorophenylmagnesium bromide. The isomer mixture was separated by theselective quaternization process to afford isoproyl3/3-(p-fluor0phenyD-1aH, SuH tropane-ZB-carboxylate, M.P. 110112 C.(from pentane), hydrochloride salt, M.P. 224 C. (dec.) (from acetone),[a] =-97.3 (1% in water).

EXAMPLE 6 (a) Methyl 8 (2 chloroethoxycarbonyl)3;8-phenyl-1aH,5aH-nortropane-Zfl-carboxylate-A mixture of 5.40 g. (0.00208 mole)of ()-methyl 3f3-phenyl-1aI-L5aI-I- tropane-ZB-carboxylate (Example 1)and 4.3 ml. (5.9 g., 0.00416 mole) of 2-chloroethyl chloroformate washeated at 100 C. for 75 minutes. The excess chloroformate was thenremoved by warming the mixture in vacuo, and the residual oil wasdissolved in ether and percolated through 200 g. of silica gel. Thefirst 400 ml. of eluate contained 4.8 g. of methyl8-(2-chloroethoxycarbonyl)-3B-phenyl- 1uH,5aH-nortropane-Zfi-carboxylateas an oil which was used without further purification in the nextreaction.

(b) Methyl 3p phenyl 1aH,SaH-nortrupaneQB-carboxylate.To a stirredsolution of 10 ml. of ethylenediamine in 800 ml. of dimethylformamide inan oxygenfree atmosphere (argon) was added 100 ml. of 0.83 N chromousperchlorate. The mixture, the temperature of which rose to 42 C., wascooled to 25 C., and 4.80 g. (0.00136 mole) of methyl8-(2-chloroethoxycarbonyl)-3fi-phenyl-laH,5aH-nortropane-2fi-carboxylate in 20 ml.

of dimethylformamide was added. This mixture was stirred for 2 hours,allowed to stand for about sixteen hours and then poured into ice-water.Ammonium carbonate (10 g.) was added and the weakly basic mixture wasextracted three times with chloroform-ethanol (2:1). The extracts weretreated with an excess of 2 N hydrochloric acid and concentrated invacuo. The pasty residue was treated with excess cold 2 N sodiumhydroxide and the product extracted with ether. The oil obtained fromthe extracts was chromatographed on silica chromatoplates to give 2.05g. of methyl 35 phenyl 1aH,5uH- nortropane-Zfi-carboxylate, which wasconverted to its hydrochloride salt monohydrate, M.P. 118-122 C. (dec.),[u] =-1l0.0 (1% in water).

EXAMPLE 7 (a) (+)-Methyl 3a hydroxy 1aH,5aH-tropane-2acarboxylate[(+)-pseudoalloecgonine methyl ester].A solution of 7.00 g. (0.0183mole) of methyl 3-oxo-laH, 5aH-tropane 2oz carboxylate levo-bitartratedihydrate [Findlay, J. Org. Chem., 22, 1385 (1957)] in ml. of water wasdiluted with 200 ml. of acetic acid, 1.0 g. of platinum oxide catalystwas added, and the mixture was hydrogenated at room temperature under apressure of 4.2 kg/em. for 19 hours. The catalyst and solvent wereremoved and the residual oil was treated with chloroform and an excessof cold 35% sodium hydroxide. The aqueous layer was extracted twice withchloroform, and the combined chloroform layers were concentrated to givean oil. This oil was dissolved in 100 ml. of ether, the solutionfiltered and the solvent evaporated to give an oil which solidified(3.05 g.). The latter was recrystallized twice from hexane, whileremoving a small amount of insoluble brown powder, to give(+)-pseudoalloecgonine methyl ester, M.P. 82.5-84.5 C., [cc] =+38.2 (1%in chloroform).

(b) (+)-Anhydroecgonine methyl ester.-A mixture of 15.7 g. (0.079 mole)of (+)-pseudoalloecgonine methyl ester and 50 ml. of phosphorusoxychloride was refluxed for 2.5 hours and then concentrated to aresidual oil by warming the mixture in vacuo. The oil was poured ontoice and the mixture made basic with 35% sodium hydroxide solution. Theproduct was extracted with two portions of ether and four portions ofchloroform and distilled, giving 8.72 g. (61%) of (+)-anhydroecgoninemethyl ester (the unnatural isomer), B.P. 67-74" C. (0.1 mm.). A centercut showed n =l.5011, [M =+38.3 (1% in chloroform).

(c) (+)-Methyl 3,8-phenyl locI-LSocI-I tropaue-Zflcarboxylate wasprepared by reacting (+)-anhydroecgo-' nine methyl ester andphenylmagnesium bromide, and was obtained in the form of its1,5-naphthalenedisulfonate salt, colorless needles, M.P. 272-274 C.(dec.), =+85.2 1% in water), the optical isomer (mirror image) of the1,S-naphthalenedisulfonate salt obtained in Example 1.

EXAMPLE 8 Methyl 3,9-(p-fluorophenyl)-1aH,5aH-tropane 2 carboxylate wasprepared from +)-anhydroecgonine methyl ester andp-fluorophenylmagnesium bromide using 6 mole percent of cuprouschloride. The temperature was held at 0 to 5 C. during ester additionand subsequent stirring. The epimers were separated on silica gel usingisopropylamine-ether-pentane (0.5:69.5:30) for elution. There was thusobtained a 9.5% yield of (+)-methyl-3B-(p-tluorophenyl)-1aH,5aH-troane-ZB-carboxylate, M.P. 9496 C. (needles from pentane), 1,5naphthalenedisulfonate salt, M.P. 292-294 C. (dec.) (needles fromacetonitrile), [a] =|-84.5 (1% in water); and()-methyl-3fl(pfluorophenyl)-1aH,5aH-tropane 2a carboxylate, M.P.71.573.5 C. (needles from pentane), [a] =-1 2 (5% in chloroform). Theseare the optical isomers (mirror images) of the compounds obtained inExample 2.

7 EXAMPLE 9 Methyl 3B (m-methoxyphenyl)-1aH,5aH-tropane-2- carboxylatewas prepared from (--)-anhydroecgonine methyl ester andm-methoxyphenylmagnesium bromide in 50% yield. The product was a 3:1mixture of the 211- and ZB-carboxylates and boiled at 159-164 C. (0.4mm). It was separated by chromatography or by selective quaternizationwith benzyl chloride in boiling acetonitrile. The quaternized2a-carboxylate was then debenzylated catalytically to regenerate thetertiary base. Thus obtained were methyl 3B-(m-methoxyphenyl)-1aH,5aH-tropane-h-carboxylate, M.P. 81-82" C. (needles from hexane), [a] -"=+4.5(1% in chloroform) and methyl 3B-(m-methoxyphenyl)-1aH,5a5H-tropane 218carboxylate, an oily base.

EXAMPLE l Methyl 3 8 (m-hydroxyphenyl)-1aH,5aH-tropane-2B-carboxylate.-A solution of 4.0 g. of methyl3,6-(mmethoxyphenyl)-1H,5dH-tropane-2p-carboxylate in 20 ml. of 48%aqueous hydrogen bromide was heated under reflux for 45 minutes. Theproduct was collected by filtration to give3,8-(m-hydroxyphenyl)-1aH,5uH-tropane- Zfl-carboxylic acid hydrobromideas colorless needles. The product was suspended in 60 ml. of methanoland the mixture saturated with gaseous hydrogen chloride. It was thenrefluxed for six hours in the presence of a slow stream of hydrogenchloride. The solution was concentrated to a residue which was madebasic with ammonium hydroxide and extracted with ether. Evaporation ofthe ether afforded methyl SB-(m-hydroxyphenyD-1aH,SaH-tropane-2fi-carboxylate which was converted to its hydrochloridesalt, 1.01 g., colorless needles, M.P. 311"C. (dec.), [a]; 1l1.3 (1% inwater).

EXAMPLE 11 Methyl 8 isopropyl-3fi-phenyl-laH,5aH-nortropane-2-carboxylate can be prepared from 8-isopropylanhydronorecgonine methylester (prepared by reacting anhydronorecgonine methyl ester withisopropyl bromide in the presence of potassium acetate indimethylformamide solution) and phenylmagnesium bromide according to thestandard procedure described above.

Similarly, methyl8-(n-hexy1)-3fi-phenyl-1uH,5aH-nortropane-Z-carboxylate can be preparedfrom 8-(n-hexy1) anhydroecgonine methyl ester and phenylmagnesiumbromide.

EXAMPLE 12 Methyl 3p (p-chlorophenyl)-1ozH,5aH-tropane-2-carboxylate canbe prepared from anhydroecgonine methyl ester andp-chlorophenylmagnesium bromide according to the standard proceduredescribed above.

EXAMPLE 13 Methyl 313 (3,4-dimethoxyphenyl)-laH,5aH-tropane-2-carb0xylate can be prepared from anhydroecgonine methyl ester and3,4-dimethoxyphenylmagnesium bromide according to the standard proceduredescribed above.

8 EXAMPLE 14 Methyl 3B (3 methoxy-4-chloropheny1)-1aH,5aH-tropane-Z-carboxylate can be prepared from anhydroecgonine methyl esterand 3-methoxy-4-chloropheny1magnesium bromide according to the standardprocedure described above.

We claim:

1. A compound selected from the group consisting of (A) a compound ofthe formula one of R and R is hydrogen and the other of R and R iscarbo-lower-alkoxy;

R" is hydrogen or lower-alkyl;

Ar is phenyl or phenyl substituted by from one to two substituentsselected from the group consisting of lower-alkyl, lower-alkoxy, fluoro,chloro and hydroxy; and

(B) a pharmaceutically acceptable acid-addition salt of a compound under(A) above.

2. A compound according to claim 1 wherein R" is methyl.

3. Lower-alkyl 3- 3-phenyl-1aH,5uH-tropane-2-carboxylate, according toclaim 2.

4. Methyl 3B-phenyl-1aH,SaH-tropane-2fi-carboxylate, according to claim3.

5. Lower alkyl 3 8-(4-fluorophenyl)-laH,5aH-tropane- 2-carboxylate,according to claim 2.

6. Methyl 35 (4-fluorophenyl)-1aH,5aH-tropane-2flcarboxylate, accordingto claim 5.

'7. Lower-alkyl 36 (methoxyphenyl)-1uH,5H-tropane-2-carboxylate,according to claim 2.

8. Lower-alkyl 35 phenyl-1aH,5aH-nortropane-2-carboxylate, according toclaim 1.

9. The process for separating the 20:- and 2i3epimers from the epimermixture of lower-alkyl 3fi-AI-1aH,5aH- tropane-Z-carboxylate, wherein Arhas the meaning given in claim 1, which comprises heating said mixturewith a lower-alkyl or benzyl halide in an inert solvent, andpartitioning the product between water and an organic solvent, therebyremoving the 2a-epimer in the form of its water-soluble quaternaryammonium salt.

References Cited UNITED STATES PATENTS 3,058,984 10/1962 Archer et al.260292 3,056,794 10/1962 Archer et a1. 260292 ALAN L. ROTMAN, PrimaryExaminer US. Cl. X.R. 424-267

